This invention relates to improving cancer cell-based immunotherapy (e.g., immunization or vaccination) comprised of administration of allogeneic cancer cells secreting a modified heat shock protein to a human subject. It is improved by frequent administration of allogeneic cancer cells to the subject, depletion of B cells in the subject before and/or during the first or at least one administration of allogeneic cancer cells, or both.
WO 99/42121 disclosed a cell-based vaccine, wherein modified heat shock protein encoded by a transfected expression construct is secreted. The vaccine may be effective to treat or prevent cancer or infectious disease. One injection of recombinant cancer cells and two injections of recombinant cancer cells separated by two weeks were described. Autologous cancer cells were preferred. By contrast, the present invention uses allogeneic cancer cells.
WO 2005/030136 disclosed inhibiting a tumor by administering a lung cancer cell genetically modified to express CD80 and HLA. The cancer cell does not secrete a modified heat shock protein.
Cancer is typically treated by surgical resection of the tumor, radiation or drugs to kill cancer cells, or a combination thereof. The immune system can inhibit the multiplication and spread of cancer cells. They may escape immuno-logic surveillance, however, by being nonimmunogenic (e.g., nonsmall cell lung cancer), which blocks priming of the immune response to generate an effective response, or being immunogenic (e.g., melanoma) but blocking the effector phase of the immune response. Alternatively, blockade of priming could be due to the tumor secreting immunosuppressive mediators or tolerizing chemokines and/or stimulation of regulatory cells, tolerogenic antigen presenting cells, or myelosuppressor cells. Active immunotherapy by administering allogeneic cancer cells could circumvent blockade, and prime the innate and/or adaptive immune response. The induction and amplification of a tumor-specific CD8+T-cell response would be especially desirable as evaluated by cytolysis of cancer cells or secretion of interferon gamma stimulated by cancer cells.
Raez et al. (J. Clin. Oncol. 22:2800-2807, 2004) described a phase I trial of an allogeneic cancer cell-based vaccine for non-small cell lung cancer in patients with advanced metastatic disease. Adenocarcinoma cell line AD100 was transfected to express CD80 and HLA-A1 or A2. Patients were immunized intradermally with 5×107 cells once every two weeks. Three immunizations represented one course of treatment. Unless a patient had no response to the initial immunization, up to three courses of treatment for a total of nine immunizations were administered. The promising results obtained using this cell-based vaccine might be improved by increasing the frequency of immunization and depleting B cells before and/or during at least one immunization.
Therefore, it is an objective of the present invention to provide improved immunotherapy (e.g., immunization or vaccination), which comprises administering allogeneic cancer cells secreting a modified heat shock protein to a human subject, by frequent administration, depletion of B cells before and/or during the initial or at least one administration, or both. Other advantages and improvements are described below or would be apparent from the disclosure herein.